Transplantation of pancreatic islet cells is a valid treatment option for selected patients with diabetes. Under current protocols, the main therapeutic goal that can be reliably achieved is improved glycemic control and prevention of severe hypoglycemic episodes. Insulin independence can only be achieved for a limited time after repeated transplantations (1) due to insufficient islet mass and progressive loss of islets over time. Therefore, efforts to improve islet transplantation focus on improving the exploitation of mechanisms governing beta cell proliferation and growth as well as islet quality (2-4).
Several growth factors that may have potential for enhancing beta cell mass have been identified (5). A natural growth factor-mediated adaptation of islet cell mass occurs due to increased demand during pregnancy as well as with obesity (6). In addition, promotion of islet cell growth has been linked to glucagon-like peptide 1 (GLP-1), obestatin and ghrelin (4, 7, 8). Surprisingly, little attention has been given to the possible role of growth hormone-releasing hormone or its agonists. In his Nobel lecture more than 60 years ago, Bernardo Houssay described the critical role of the “hypophysis in carbohydrate metabolism and in diabetes” (9). He observed that extracts of the anterior pituitary gland can produce a stimulation and hyperplasia of islets under certain conditions. With the advent of stem cell biology and regenerative medicine, there has now been a renewed interest in elucidating the role of hypothalamic-pituitary-growth factors in islet cell regulation.
Growth-hormone-releasing-hormone (GHRH) stimulates the release of growth hormone (GH) from the pituitary and has been the focus of intense studies since its structure was described in 1982 (10, 11). The full biological activity of GHRH resides in the N-terminal 1-29 amino acid sequence of this peptide (12). GHRH and the pituitary type of GHRH-receptor as well as its splice variants are expressed in many human tissues, i.e. ovary, testis, pancreas, colon, esophagus, breast, kidney, liver, prostate, lungs and thymus (13-15).
A recent study has shown that rat GHRH promoted survival of cardiomyocytes in vitro and protected rat hearts from ischemia-reperfusion injury (16). The detection of the GHRH receptor (GHRH-R) on the cardiomyocyte sarcolemma supports the view that GHRH may elicit direct signal transduction within the heart, independent of the GH/IGF-1 axis per se (17). Synthetic GHRH agonists, such as JI-34, JI-36, JI-38 (GHRH-A), are more potent and longer-acting than native GHRH (18, 19). Recently, it was demonstrated that GHRH-agonist JI-38 has a favorable cardiac effect, attenuating infarct size as well as the progressive decrease of cardiac structure and function following myocardial infarction (MI) (16).